rs4103

Variant names:

• chr13-110445879-C-T
• rs4103
• NM_001846.4:c.1008C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001846.4(COL4A2):​c.1008C>T​(p.Pro336Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 1,613,490 control chromosomes in the GnomAD database, including 227,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18597 hom., cov: 32)
  • Exomes 𝑓: 0.53 (208570 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.347
• Publications: 33 publications found

Genes affected

COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

COL4A2 Gene-Disease associations (from GenCC):

• porencephaly 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• COL4A1 or COL4A2-related cerebral small vessel disease

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 13-110445879-C-T is Benign according to our data. Variant chr13-110445879-C-T is described in ClinVar as Benign. ClinVar VariationId is 311117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.347 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.1008C>T	p.Pro336Pro	synonymous	Exon 17 of 48	NP_001837.2	P08572

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.1008C>T	p.Pro336Pro	synonymous	Exon 17 of 48	ENSP00000353654.5	P08572
	COL4A2	ENST00000714399.1		c.1008C>T	p.Pro336Pro	synonymous	Exon 17 of 49	ENSP00000519666.1	A0AAQ5BHW7
	COL4A2	ENST00000400163.8	TSL:5	c.1008C>T	p.Pro336Pro	synonymous	Exon 17 of 48	ENSP00000383027.4	P08572

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74703 AN: 151908 Hom.: 18579 Cov.: 32

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.642

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.484

GnomAD2 exomes AF: 0.511 AC: 127547 AN: 249516 AF XY: 0.514

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.495

Gnomad ASJ exome AF: 0.426

Gnomad EAS exome AF: 0.525

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.538

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.533 AC: 778336 AN: 1461464 Hom.: 208570 Cov.: 49 AF XY: 0.533 AC XY: 387803 AN XY: 727064

African (AFR) AF: 0.397 AC: 13301 AN: 33476

American (AMR) AF: 0.493 AC: 22025 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 11208 AN: 26126

East Asian (EAS) AF: 0.567 AC: 22514 AN: 39698

South Asian (SAS) AF: 0.524 AC: 45211 AN: 86234

European-Finnish (FIN) AF: 0.498 AC: 26592 AN: 53412

Middle Eastern (MID) AF: 0.411 AC: 2371 AN: 5768

European-Non Finnish (NFE) AF: 0.543 AC: 604168 AN: 1111654

Other (OTH) AF: 0.513 AC: 30946 AN: 60382

GnomAD4 genome AF: 0.492 AC: 74747 AN: 152026 Hom.: 18597 Cov.: 32 AF XY: 0.491 AC XY: 36457 AN XY: 74272

African (AFR) AF: 0.401 AC: 16628 AN: 41462

American (AMR) AF: 0.482 AC: 7366 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1561 AN: 3470

East Asian (EAS) AF: 0.535 AC: 2760 AN: 5156

South Asian (SAS) AF: 0.537 AC: 2582 AN: 4804

European-Finnish (FIN) AF: 0.495 AC: 5237 AN: 10586

Middle Eastern (MID) AF: 0.438 AC: 128 AN: 292

European-Non Finnish (NFE) AF: 0.543 AC: 36887 AN: 67966

Other (OTH) AF: 0.480 AC: 1014 AN: 2112

Alfa AF: 0.514 Hom.: 35977

Bravo AF: 0.482

Asia WGS AF: 0.495 AC: 1723 AN: 3476

EpiCase AF: 0.530

EpiControl AF: 0.525

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Porencephaly 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.9
DANN	Benign	0.79
PhyloP100		-0.35
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4103; hg19: chr13-111098226; COSMIC: COSV64635223;